Download Cardiovascular disease in CKD

Cardiovascular complications
in Chronic Kidney Disease
- Hopes and Challenges
Nihil Chitalia
Consultant Nephrologist
Epsom and St. Heliers’ University Hospital NHS trust
CV complications in CKD
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•
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•
Magnitude
Mechanisms
Evidence base
Conclusion
Case Presentation
Mrs. Kamalben Patel, 42 year female, no DM
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 29, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 100 mg/mmol
Medications: aspirin 75, amlodipine 10 mg, ramipril 5 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop I 65
– What is the cause?
NSTEMI
Magnitude of CV disease in CKD
Mortality and CV events in CKD
Adjusted hazard ratio for death from any cause
over 2.8years (n=1120295)
Adjusted hazard ratio for cardiovascular events
3.4
5.9
2.8
2
3.2
1
1.2
>60
45-59
1.4
1
1.8
30-44
15-29
<15
GFR ml/min/1.73sq.m
>60
45-59
30-44
15-29
<15
GFR ml/min/1.73sq.m
eGFR ml/min
Risk of CV death *
45-59
40%
30-44
100%
15-29
180%
<15
240%
*Ref group: >60ml/min
Go NEJM 2004;351;1296
Prevalence of CVD in CKD
Prevalance (%) of CVD at baseline
44
34.2
17.8
>60
30-59
<30
Glomerular filtration rate
Not just higher incidence but also higher prevalence of CVD in CKD
Banerjee Int J Urol Nephrol 2009
Risk of Death vs. ESRD
O’Hare et al, JASN 2007
Young vs. old
27 years
77 years
Both on dialysis
who is more likely to die compared to somebody of similar age but no CKD?
Young vs. old
More at risk
compared to
non CKD of
same age
CVD mortality is high on Dialysis
CVD mortality in dialysis patients (USRDS) compared to the general
population (NCHS)
Foley et. al., 1998 Am J Kid Disease 32
Case Presentation
• 68 year male on HD for 3 years
• Attended regular dialysis session in the evening
• Found dead the following day
Cause of death?
1.
2.
3.
4.
MI
Brain haemorrage
Pulmonary embolism
Sudden cardiac death
Cardiovascular mortality in HD
USRDS: >50% of all deaths are cardiovascular
– 20% of all CV deaths are due to MI
– 65% of all CV deaths are due to arrhythmias
uncertain
malignancy
others
cardiovascular
infection
Deaths in prevalent HD patients 1995-1999 (n=1453)
Rocco et al AJKD 2002;39:146
Frequency of cardiac arrests
increases with time on HD
Events per 1000 patient years
1st year
4th Year
DM
110
208
Non DM
70
131
• 1.6x higher in DM
• 2 x higher in 4th year vs. 1st year
Herzog CA KI 2003; 84:S197
Cardiac Fibrosis in ESRD patients
14.2%
subendocardial fibrosis %
14.2%
Diffuse fibrosis %
134 HD patients studies with Cardiac MR
- Mark PB, Kid Int 2006
Cardiac fibrosis a strong predictor
of death in ESRD
40 HD patients with DCM.
No CAD
vs.
50 nonHD patients with
DCM
Aoki; KI (2005) 67:333
Case Presentation
Mrs. Kamalben Patel, 42 year female, no DM
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 29, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 100 mg/mmol
Medications: aspirin 75, amlodipine 10 mg, ramipril 5 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
– What is the cause?
– What is her prognosis?
NSTEMI
Mortality post MI
2y mortality (%) post MI in CKD
73
45
33.6
16
HD
Gottlieb NEJM 339: 489
CKD 4
Tx
General
Population
Herzog AJKD 2000;36 145
Herzog NEJM 1998;339 799
Risk factor inverventions….
Case Presentation
Mrs. Kamalben Patel, 42 year female, no DM
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 29, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 100 mg/mmol
Medications: aspirin 75, amlodipine 10 mg, ramipril 5 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
– What is the cause?
– What is her prognosis?
NSTEMI
Obesity and CV death in ESRD
Inverse epidemiology in ESRD patients, not so in predialysis CKD
Kalantar-Zadeh K 2005
Case Presentation
Mrs. Kamalben Patel, 42 year female, no DM
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 23, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
• Urinary Protein:creatinine ratio 100mg/mmol
Medications: aspirin 75, amlodipine 10 mg, ramipril 10 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
NSTEMI
Dual Therapy ACE- & A II RB ?
Telmisartan 80mg vs. Ramipril 10mg vs. Temisartan 80+ Ramipril 10
ONTARGET study NEJM 2008
Dual Therapy ACE- & A II RB
Change in BP in the 3 treatment groups
Change in BP
Ramipril
Telmisartan
Combination
Systolic mmHg
-6
-6.9
-6.4
Diastolic mmHg
-4.6
-5.2
-6.0
Higher Hypotension, syncope and diarrhoea in combination therapy group
ONTARGET study NEJM 2008
Dual therapy with ACE- & A II RB
Dual therapy is associated 24% higher risk of adverse worse renal outcomes
(Doubling of creatinine or initiation of dialysis)
Mann JF, Lancet 2008
Case Presentation
Mrs. Kamalben Patel, 42 year female CRF, no DM, first presentation
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 23, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 100 mg/mmol
Medications: aspirin 75, amlodipine 10 mg, ramipril 10 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
NSTEMI
Lipids and CV risk in ESRD
1255 type II DM HD patients
20 mg Atorvastatin vs. Placebo
LDL>2.1 mmol/L
4 year F/U
4D Study NEJM 2005
Lipids and CV risk in ESRD
2766 HD patients
10 mg Rosuvastatin vs. Placebo
5 years f/u
28% DM
AURORA study, NEJM 2009
Lipids and CV risk in CKD
•9000 CKD patients (6000 predialysis CKD; 3000 ESRD patients)
•20 mg Simvastatin + 10 mg Ezetimibe vs. Placebo
SHARP: Major Atherosclerotic Events
Proportion suffering event (%)
25
Risk ratio 0.83 (0.74 – 0.94)
Logrank 2P=0.0022
20
Placebo
15
Eze/simv
10
5
0
0
1
2
3
Years of follow-up
4
5
Case Presentation
Mrs. Kamalben Patel, 42 year female CRF, no DM, first presentation
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 23, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 50 mg/mmol
Medications: aspirin 75, amlodipine 10 mg, ramipril 10 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
NSTEMI
Inflammation as risk factor
CRP and SCD in 1041
HD patients
2.09
1.24
1
1st Tertile 2nd Tertile 3rd Tertile
Increasing sudden cardiac deaths with rising CRP
Parekh KI 2008 74;1335
Case Presentation
Mrs. Kamalben Patel, 42 year female CRF, no DM, first presentation
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 23, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 50 mg/mmol
Medications: aspirin 75, amlodipine 10 mg, ramipril 10 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
NSTEMI
PROTOCOL FOR BLOOD PRESSURE CONTROL IN RENAL FAILURE PATIENTS
Target <130/80 mm Hg
With all steps
Salt restriction < 100 mmol/day (< 6g NaCl or <2.4
g Na+/day), Exercise 30 mins/daily, Stop smoking
Step 1
Ramipril 5 mg od or Irbesartan 150 mg od
Step 2
Frusemide 40 od-bd
Step 3
Ramipril 10 mg od or Irbesartan 300 mg od
Step 4
Amlodipine 5 mg od or Nifedipine LA 30 mg od
Step 5
Amlodipine 10 mg od or Nifedipine LA 90 mg od
Step 6
Doxazocin XL 4 mg od or Metoprolol 50 mg bd
Step 7
Doxazocin XL 8 mg od or Metoprolol 100 mg bd
Step 8
Moxonidine/Hydralazine/Minoxidil
On average a patient may need three antihypertensives
Move to the next step if one step is not tolerated
Case Presentation
Mrs. Kamalben Patel, 42 year female CRF, no DM, first presentation
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 23, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 50 mg/mmol
• Calcium 2.5mmol/L, Phos 2.2mmol/L, PTH 200
Medications: aspirin 75, amlodipine 10 mg, ramipril 10 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
NSTEMI
Vascular pathology in ESRD
Vascular calcification in CKD
Medial calcification in CKD patients
Von Kossa Stain
N Chitalia, et al. Accepted for Publication in Seminars in Dialysis
Extraskeletal manifestation of renal
bone disease
Brenner & Rector’s. The Kidney. Seventh Edition 2004
CV effects of medial
calcification/Arteriosclerosis
Keith A, Hruska et al. Kidney International. 74(2):148-57, 2008 Jul
1.50
1.39**
1.25
1.18*
1.00
1.00
1.00
0.36-1.45
1.49-1.78
1.02
1.81-2.10
2.13-2.52
Serum Phosphorus Quintile (mmol/L)
2.55-5.46
Relative Mortality Risk (RR)
Relative Mortality Risk (RR)
Effects of Hyperphosphatemia and elevated
Ca x P product on mortality in CKD
1.50
1.34*
1.25
1.13
1.08
1.06
1.00
1.00
1.13-3.39
3.47-4.20
4.28-4.84
4.92-5.81
5.89-10.65
Ca x P Product Quintile (mmol2/L2)
P=0.03 **P<0.0001 (N=6407)
Block GA, et al. Am J Kidney Dis. 1998;31:607-617
NKF-K/DOQI bone metabolism
guidelines
Parameter
Target range
150–300 pg/mL
iPTH
16.5–33.0 pmol/L
Ca x P
< 4.51 mmol2/L2
Phosphorus
1.10–1.78 mmol/L
‘Corrected’ calcium 2.10–2.37 mmol/L
Aluminium level <2.2 mmol/l (60mg/l) (ferritin >100) – RA standards 2002
Calcium dosage Less than 1500mg elemental calcium
Eknoyan G et al. Am J Kidney Dis 2003;42(Suppl 3):1–201
Case Presentation
Mrs. Kamalben Patel, 42 year female CRF, no DM, first presentation
•
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 23, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 50 mg/mmol
Calcium 2.5mmol/L, Phos 2.2mmol/L, PTH 200
Medications: aspirin 75, amlodipine 10 mg, ramipril 10 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
NSTEMI
Anaemia correction
4038 diabetics CKD patients followed for 4 y
EPO group to achieve Hb 13 g%
Pfeffer NEJM 2009 361 2019
Case Presentation
Mrs. Kamalben Patel, 42 year female CRF, no DM, first presentation
•
•
•
•
Creatinine 250µmol/L, Haemoglobin 10.5 g/dL
Non smoker, BMI 23, BP 145/85, Cholesterol 5.2 mmol/L, CRP 5.3
Urinary Protein:creatinine ratio 50 mg/mmol
Calcium 2.5mmol/L, Phos 2.2mmol/L, PTH 200
Medications: aspirin 75, amlodipine 10 mg, ramipril 10 mg
•
At present her eGFR is 16 ml/min/1.73m2
•
She presents to A&E with chest pain; ECG T inv V4-V6; trop 1.2
• Does coronary intervention help?
NSTEMI
Benefits of coronary PCI in HD
259 patients followed for 5 years
Yasuda JASN 2006 17 2322
CABG vs PCI in ESRD
CABG
PTCA
Stent
15700 patients followed for 4 years USRDS
Herzog Circulation 2002 106 2207
So what did I say…..
• CKD is a CVD risk – graded relationship but all stages
• Risk factors of CVD in CKD – traditional and non
traditional
• SCD commonest cause of CV mortality in ESRD
• Treatment of hypercholesterolemia probably beneficial in
predialysis CKD, but no evidence in ESRD (for primary
prevention)
• Phosphate control is important in CKD to prevent CV
mortality
• Coronary revascularisation beneficial